DNA repair genetic polymorphisms and breast cancer in the Portuguese population

Breast cancer is the leading cause of death among women in developing countries. Approximately 10% of all cases of breast cancer are inherited, exhibiting a familial pattern of incidence, which have been attributable to mutations in high penetrance susceptibility genes, such as BRCA1 and BRCA2. However, these mutations only account to approximately 25% of the families with inherited breast cancer; therefore, identification of genes that are associated with a small or modest cancer risk is an important step to define breast cancer risk. It has been determined that different genetic backgrounds due to the combination of subtle sequence variants or polymorphisms, within low-penetrance genes, can explain the remaining familial and sporadic breast cancer risks. Many environmental factors have been associated with risk of breast cancer development, being sources of a wide range of DNA damage. The cellular response to DNA damage and its ability to maintain genomic integrity by DNA repair are crucial in preventing cancer initiation and progression. Previous studies have suggested an influence of gene variants in different DNA repair pathways regarding their capacity to repair. Therefore, polymorphisms in these genes may contribute to breast cancer susceptibility. The general aim of this thesis was to understand the association of different polymorphisms ( XRCC1 Arg399Gln, XPD Lys751Gln, RAD51 G135C, XRCC3 Thr241Met, TP53 Arg72Pro and TP53 PIN3 Ins16bp) belonging to the DNA damage signalling and repair mechanisms with breast cancer susceptibility, in familial and sporadic breast cancer, in the Portuguese population. Furthermore, we intended to characterize the protein expression profiles of the most relevant polymorphisms found in breast cancer patients and human breast cancer cell lines, correlating the protein expression profile with the polymorphic status. Our findings identified RAD51 G135C polymorphism as a real risk modifier in familial breast cancer cases. Furthermore, we pointed out that XRCC1 Arg399Gln and XRCC3 Thr241Met polymorphisms as important biomarkers to sporadic breast cancer susceptibility. Moreover, our results also showed that TP53 PIN3 A2 allele in a haplotype combination confer increased breast cancer susceptibility among women carriers of FH of the disease. According to our findings from the association between the polymorphism and the clinicalpathological parameters from breast cancer patients, we clearly underlined the role of XRCC1 Arg399Gln and RAD51 G135C polymorphisms in the prediction of breast tumor aggressiveness and patients’ survival. Furthermore, our results suggested TP53 Arg72Pro and PIN3 Ins16bp polymorphisms as predictive factors of presence of lymph node metastases. Additionally, we demonstrated that XRCC1, XRCC3 and P53 expressions did not correlate with the respective genetic polymorphisms analysed, in breast cancer patients and in human breast cancer cell lines.

Name thesis:degree_name

Doutoramento em Ciências da Saúde (especialidade em Ciências Biológicas e Biomédicas)

Year dc:date.issued

2007

Author dc:creator

• Costa, Sandra Maria Araújo da

Advisors dc:contributor.advisor

• Leão, Cecília
• Schmitt, Fernando C.

Statement dc:rights

• openAccess

Language dc:language.iso

eng

Handle dc:identifier.uri

https://hdl.handle.net/1822/7099

OAI record oai:identifier

http://repositorium.sdum.uminho.pt/oai/request?verb=GetRecord&metadataPrefix=dim&identifier=oai%3Arepositorium.uminho.pt%3A1822%2F7099